Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers

ABSTRACT

The present invention provides novel solid pharmaceutical dosage forms for oral administration comprising a bisphosphonate, or a pharmaceutically acceptable salt thereof, which bisphosphonate is present in an amount not therapeutically effective when the bisphosphonate is orally administered alone; and a modified amino acid carrier, or a pharmaceutically acceptable salt thereof, which modified amino acid carrier is present in an amount effective to facilitate absorption of the bisphosphonate in the gastrointestinal tract such that the bisphosphonate is therapeutically effective. The ratio of bisphosphonate to modified amino acid carrier is from about 1:30 to about 1:1, respectively. These novel solid pharmaceutical dosage forms are useful in the treatment or control of bone diseases and particular disorders in calcium metabolism, including, for example, osteoporosis, hypercalcaemia of cancer, and the treatment of metastatic bone pain. The present invention also provides a method for treating these diseases employing the solid pharmaceutical dosage forms and a method for preparing the pharmaceutical dosage forms.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/710,899, filed Aug. 24, 2005 and U.S. Provisional Application No.60/763,982, filed Feb. 1, 2006. The entire contents of theabove-identified applications are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions and methodsfor making same.

BACKGROUND OF THE INVENTION

Bisphosphonates

Bisphosphonates (diphosphonates) are synthetic compounds characterizedby two carbon to phosphorus bonds:(HO)₂(O)P—C(R₁)(R₂)—P(O)(OH)₂

Bisphosphonates are analogs of inorganic pyrophosphate.(HO)₂(O)P—O—P(O)(OH)₂

Inorganic pyrophosphate is a normal by-product of human metabolism andis produced by anabolic processes. Inorganic pyrophosphate is readilyhydrolyzed to its constituent phosphate groups. When the linking oxygenatom in the pyrophosphate molecule is replaced by a carbon atom, thebisphosphonate formed is resistant to hydrolysis and is chemicallystable. Like pyrophosphate, bisphosphonates bind to the hydroxyapatitecrystals of bone and prevent their growth and their dissolution.

Bisphosphonates are highly effective in enhancing bone mineral density(BMD) and decreasing bone fracture rates. Bisphosphonates are effectivedrugs for bone disorders characterized by increased bone resorption,such as Paget's disease, osteoporosis, hypercalcaemia of cancer,metastatic bone disease, multiple myeloma, and bony metastases.Bisphosphonates are also effective in the treatment of bone painaccompanying these disorders.

Due to their stability, the bisphosphonates are absorbed, stored andexcreted unchanged. Bisphosphonates are characterized by poor intestinalabsorption but highly selective localization and prolonged storage inbone. Absorption is believed to take place in the stomach and uppersmall intestine, and is reduced if the drug is given with antacids,calcium, magnesium, iron supplements, or vitamins with minerals. Aperiod of about 2 hours of fasting is generally recommended beforetaking the bisphosphonate and a period of about 30-60 minutes of sittingor standing upright is generally recommended after taking thebisphosphonate to avoid irritation of the throat and esophagus.Bisphosphonates are therefore not administered at meal times or withdairy products.

United States patent publication number 20040097468, paragraph 10,discloses that the absorption of bisphosphonates is usually less than 1%of that of the orally or intravenously administered dose and thereforeit may take several months or up to a year or more to get an adequateamount of a bisphosphonate into bone to be therapeutically effective.

Modified Amino Acid Carriers

Delivery of an active agent is often limited by biological, chemical,and/or physical barriers. The barrier may be imposed by the nature ofthe active agent, by the nature of the target, by the environment of thetarget, or by the environment through which delivery of the active agentoccurs. Biological barriers include the properties of the active agent;chemical barriers include pH variations, lipid bilayers, and degradingenzymes; and physical barriers include organ membranes that must betraversed before the active agent can reach the target. These barriersare of particular significance when the active agent is delivered orallybecause of varying pH in the gastrointestinal tract, digestive enzymes,and impermeable gastrointestinal membranes.

Many methods for orally administering a pharmacological agent rely uponthe co-administration of an adjuvant to artificially increase thepermeability of the intestinal wall or the co-administration of anenzymatic inhibitor. The use of liposomes and microspheres of artificialpolymers of mixed amino acids (proteinoids) has been disclosed toprotect active agents in drug delivery systems. Modified amino acidcarriers have also been disclosed to deliver active agents and aredisclosed in U.S. Pat. Nos. 5,650,386, 5,866,536, 5,965,121, 5,989,539,6,001,347, 6,344,213, 6,346,242, 6,623,731, and 6,699,467. Otherdelivery agents have been disclosed in U.S. Pat. Nos. 5,451,410,5,766,633, 5,792,451, and 6,099,856. Compositions for deliveringbisphosphonates are disclosed in United States patent publication No.2004/0147484.

SUMMARY OF THE INVENTION

The present invention provides a solid pharmaceutical dosage form fororal administration comprising:

(a) a bisphosphonate, or a pharmaceutically acceptable salt thereof,which bisphosphonate is present in an amount not therapeuticallyeffective when the bisphosphonate is orally administered alone; and

(b) a modified amino acid carrier, or a pharmaceutically acceptable saltthereof, which modified amino acid carrier is present in an amounteffective to facilitate absorption of the bisphosphonate in thegastrointestinal tract such that the bisphosphonate is therapeuticallyeffective; wherein the ratio of bisphosphonate to modified amino acidcarrier is from about 1:30 to about 1:1, respectively.

The present invention also provides a method for treating osteoporosiscomprising administering to a subject, in need thereof, a solidpharmaceutical dosage form for oral administration comprising:

(a) a bisphosphonate, or a pharmaceutically acceptable salt thereof,which bisphosphonate is present in an amount not therapeuticallyeffective when the bisphosphonate is orally administered alone; and

(b) a modified amino acid carrier, or a pharmaceutically acceptable saltthereof, which modified amino acid carrier is present in an amounteffective to facilitate absorption of the bisphosphonate in thegastrointestinal tract such that the bisphosphonate is therapeuticallyeffective;

wherein the ratio of bisphosphonate to modified amino acid carrier isfrom about 1:30 to about 1:1, respectively.

The present invention further provides a method for treatinghypercalcemia of cancer comprising administering to a subject, in needthereof, a solid pharmaceutical dosage form for oral administrationcomprising:

(a) a bisphosphonate, or a pharmaceutically acceptable salt thereof,which bisphosphonate is present in an amount not therapeuticallyeffective when the bisphosphonate is orally administered alone; and

(b) a modified amino acid carrier, or a pharmaceutically acceptable saltthereof, which modified amino acid carrier is present in an amounteffective to facilitate absorption of the bisphosphonate in thegastrointestinal tract such that the bisphosphonate is therapeuticallyeffective;

wherein the ratio of bisphosphonate to modified amino acid carrier isfrom about 1:30 to about 1:1, respectively.

The present invention still further provides a method for treatingmetastatic bone pain comprising administering to a subject, in needthereof, a solid pharmaceutical dosage form for oral administrationcomprising:

(a) a bisphosphonate, or a pharmaceutically acceptable salt thereof,which bisphosphonate is present in an amount not therapeuticallyeffective when the bisphosphonate is orally administered alone; and

(b) a modified amino acid carrier, or a pharmaceutically acceptable saltthereof, which modified amino acid carrier is present in an amounteffective to facilitate absorption of the bisphosphonate in thegastrointestinal tract such that the bisphosphonate is therapeuticallyeffective;

wherein the ratio of bisphosphonate to modified amino acid carrier isfrom about 1:30 to about 1:1, respectively.

The present invention still further provides a method for preparing asolid pharmaceutical dosage form for oral administration comprisingadmixing:

(a) a bisphosphonate, or a pharmaceutically acceptable salt thereof,which bisphosphonate is present in an amount not therapeuticallyeffective when the bisphosphonate is orally administered alone; and

(b) a modified amino acid carrier, or a pharmaceutically acceptable saltthereof, which modified amino acid carrier is present in an amounteffective to facilitate absorption of the bisphosphonate in thegastrointestinal tract such that the bisphosphonate is therapeuticallyeffective;

wherein the ratio of bisphosphonate to modified amino acid carrier isfrom about 1:30 to about 1:1, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a solid pharmaceutical dosage form fororal administration comprising a bisphosphonate, or a pharmaceuticallyacceptable salt thereof, which bisphosphonate is present in an amountnot therapeutically effective when the bisphosphonate is orallyadministered alone; and a modified amino acid carrier, or apharmaceutically acceptable salt thereof, which modified amino acidcarrier is present in an amount effective to facilitate absorption ofthe bisphosphonate in the gastrointestinal tract such that thebisphosphonate is therapeutically effective. The ratio of bisphosphonateto modified amino acid carrier is from about 1:30 to about 1:1,respectively. These novel solid pharmaceutical dosage forms are usefulin the treatment or control of bone diseases characterized by increasedbone resorption, such as osteoporosis and hypercalcaemia of cancer, aswell as the treatment or control of pain that accompanies suchdisorders. The present invention also provides a method for treatingsuch disorders employing the solid pharmaceutical dosage forms and amethod for preparing the pharmaceutical dosage forms.

Oral administration of the bisphosphonate with the modified amino acidcarrier results in an increased bioavailability of the bisphosphonatecompared to oral administration of the bisphosphonate alone, therebyenabling a lowering of the dose of the bisphosphonate while stillachieving equivalent efficacy of the bisphosphonate. Oral administrationof the bisphosphonate with the modified amino acid carrier may result ina reduction of the approximately 2 hour period of fasting before takingthe bisphosphonate and is expected to reduce the approximately 30-60minute period of sitting or standing upright after taking thebisphosphonate.

As used herein, the following terms have the given meanings:

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviations,per practice in the art. Alternatively, “about” with respect to theformulations can mean a range of up to 10%, preferably up to 5%.

The term “an amount effective to facilitate absorption of thebisphosphonate in the gastrointestinal tract such that thebisphosphonate is therapeutically effective” as applied to a modifiedamino acid carrier means an amount of the carrier that increasesabsorption of the bisphosphonate in the gastrointestinal tract such asto reduce the amount of bisphosphonate as compared to the amount ofbisphosphonate required if administered alone to achieve a therapeuticeffect.

The term “bisphosphonate” (diphosphonate) refers to compoundscharacterized by the formula: (HO)₂(O)P—C(R₁)(R₂)—P(O)(OH)₂, includingpharmaceutically acceptable salts, racemic mixtures, and pureenantiomers thereof, wherein R₁ and R₂ are defined below.

The term “bisphosphonate is present in an amount not therapeuticallyeffective when the bisphosphonate is orally administered alone” means anamount of a bisphosphonate, or a pharmaceutically acceptable saltthereof, which is not effective to treat, prevent, alleviate orameliorate symptoms of disease. For example, the therapeuticallyeffective amount of ibandronate for the treatment of osteoporosis is 2.5mg daily or 150 mg monthly, as measured by the weight of the free acid.Amounts of ibandronate less than the above, for their respective dosageperiods, would not be considered therapeutically effective. “[W]hen thebisphosphonate is orally administered alone” means when thebisphosphonate is not orally administered with an agent that facilitatesabsorption of the bisphosphonate in the gastrointestinal tract. Thisterm does not exclude conventional additives normally included in suchformulations including, but not limited to, lactose monohydrate,croscarmellose sodium, povidone, water, sodium stearyl fumarate, and thelike. Preferred oral dosage forms are tablets, most preferably tabletscontaining povidone.

The term “intimate contact” means a close physical association betweenthe bisphosphonate and the modified amino acid carrier. Such intimatecontact may be achieved by granulation, spray drying, fluid bed coating,fluid bed layering, and the like, of the bisphosphonate with themodified amino acid carrier.

The term “modified amino acid carriers” refers to modified amino acids,preferably ω-amino acids, modified by acylation or sulfonation of theamino group, particularly with phenyl or cyclohexyl groups, wherein thephenyl or cyclohexyl groups may contain a variety of substituents suchas hydroxyl, methyl, fluoro, and/or chloro.

The term “pharmaceutically acceptable,” such as pharmaceuticallyacceptable carrier, excipient, etc., means pharmacologically acceptableand substantially non-toxic to the subject to which the particularcompound is administered.

The term “pharmaceutically acceptable salt” refers to conventionalacid-addition salts or base-addition salts that retain the biologicaleffectiveness and properties of the compounds of the present inventionand are formed from suitable non-toxic organic or inorganic acids ororganic or inorganic bases. Sample acid-addition salts include thosederived from inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid andnitric acid, and those derived from organic acids such asp-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalicacid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid,and the like. Sample base-addition salts include those derived fromammonium, potassium, sodium, and quaternary ammonium hydroxides, such asfor example, tetramethylammonium hydroxide. Chemical modification of apharmaceutical compound (i.e., drug) into a salt is a technique wellknown to pharmaceutical chemists to obtain improved physical andchemical stability, hygroscopicity, and solubility of compounds. See,e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug DeliverySystems (6^(th) Ed. 1995) at pp. 196 and 1456-1457.

The term “prodrug” refers to compounds that undergo biotransformationprior to exhibiting their pharmacological effects. The chemicalmodification of drugs to overcome pharmaceutical problems has also beentermed “drug latentiation.” Drug latentiation is the chemicalmodification of a biologically active compound to form a new compound,which upon in vivo enzymatic attack will liberate the parent compound.The chemical alterations of the parent compound are such that the changein physicochemical properties will affect the absorption, distributionand enzymatic metabolism. The definition of drug latentiation has alsobeen extended to include nonenzymatic regeneration of the parentcompound. Regeneration takes place as a consequence of hydrolytic,dissociative, and other reactions not necessarily enzyme mediated. Theterms prodrugs, latentiated drugs, and bio-reversible derivatives areused interchangeably. By inference, latentiation implies a time lagelement or time component involved in regenerating the bioactive parentmolecule in vivo. The term prodrug is general in that it includeslatentiated drug derivatives as well as those substances that areconverted after administration to the actual substance which combineswith receptors. The term prodrug is a generic term for agents, whichundergo biotransformation prior to exhibiting their pharmacologicalactions.

The term “SNAC” as used herein refers to N-(8-[2-hydroxybenzoyl]-amino)caprylic acid and pharmaceutically acceptable salts thereof, includingits monosodium and disodium salt. The term “SNAC free acid” refers toN-(8-[2-hydroxybenzoyl]-amino) caprylic acid. Unless otherwise noted,the term “SNAC” refers to all forms of SNAC, including all amorphous andpolymorphic forms of SNAC, such as SNAC trihydrate and those describedin U.S. Ser. Nos. 60/619,418 and 60/569,476, both of which, to theextent necessary, are hereby incorporated by reference.

The term “SNAC trihydrate” as used herein refers to a crystalline formof SNAC in which three molecules of water are associated with eachmolecule of SNAC. SNAC can be prepared by the procedures described inU.S. Pat. No. 5,650,386 and International Publication Nos. WO00/46182and WO00/59863).

The term “therapeutically effective amount” with respect to abisphosphonate means an amount of the compound, or a pharmaceuticallyacceptable salt thereof, which is effective to treat, prevent, alleviateor ameliorate symptoms of disease, either alone or in combination with acarrier, such as a modified amino acid carrier.

As set out above, the present invention provides a novel solidpharmaceutical dosage form for oral administration comprising abisphosphonate, or a pharmaceutically acceptable salt thereof, whichbisphosphonate is present in an amount not therapeutically effectivewhen the bisphosphonate is orally administered alone; and a modifiedamino acid carrier, or a pharmaceutically acceptable salt thereof, whichmodified amino acid carrier is present in an amount effective tofacilitate absorption of the bisphosphonate in the gastrointestinaltract such that the bisphosphonate is therapeutically effective. Theratio of bisphosphonate to modified amino acid carrier is from about1:30 to about 1:1, respectively. Preferably, the pharmaceutical dosageform is administered to a mammal, more preferably, the pharmaceuticaldosage form is administered to a human.

The bisphosphonates in the present invention may be selected from a widevariety of bisphosphonates and pharmaceutically acceptable saltsthereof. Bisphosphonates may be represented by the formula:(HO)₂(O)P—C(R₁)(R₂)—P(O)(OH)₂. In the above formula, R₁ may be selectedfrom the group consisting of OH, Cl, and H; and R₂ may be selected fromthe group consisting of (CH₂)₃NH₂, Cl, CH₂-1-pyrrolidinyl, CH₃,CH₂CH₂N(CH₃) (CH₂CH₂CH₂CH₂CH₃), N-cycloheptyl, H, (CH₂)₅NH₂,(CH₂)₂N(CH₃)₂, (CH₂)₂NH₂, CH₂-3-pyridinyl, S-4-chlorophenyl,CH₂-2-imidazo-pyridinyl, and CH₂-2-imidazolyl. Illustrative nonlimitingexamples of bisphosphonates include alendronate [Fosamax®, R₁=OH,R₂═(CH₂)₃NH₂], clodronate [R₁═C₁, R₂=Cl], EB-1053 [R₁═OH,R₂═CH₂-1-pyrrolidinyl], etidronate [Didrocal®, R₁=OH, R₂=CH₃],ibandronate [Boniva®, R₁=OH, R₂=CH₂CH₂N(CH₃) (CH₂CH₂CH₂CH₂CH₃)],incadronate [R₁=H, R₂=N-cycloheptyl], medronate [R₁=H, R₂=H],neridronate [R₁=OH, R₂=(CH₂)₅NH₂], olpadronate [R₁=OH,R₂=(CH₂)₂N(CH₃)₂], pamidronate [Aredia®, R₁=OH, R₂=(CH₂)₂NH₂],risedronate [Actonel®, R₁=OH, R₂=CH₂-3-pyridinyl], tiludronate [Skelid®,R₁=H, R₂=S-4-chlorophenyl], YH529 [R₁=OH, R₂=CH₂-2-imidazo-pyridinyl],and zoledronate [Zometa®, R₁=OH, R₂=CH₂-2-imidazolyl]. Preferably, thebisphosphonate is alendronate or ibandronate, or a pharmaceuticallyacceptable salt thereof. More preferably, the bisphosphonate isibandronate, or a pharmaceutically acceptable salt thereof.

Bisphosphonates inhibit osteoclast-mediated bone resorption. Inosteoporosis, where osteoclasts break down bone quickly, inhibition ofthis pathway has been shown to slow bone turnover leading not only to anattenuation of turnover but also to a mean increase in bone mass.Bisphosphonates have a high binding affinity for hydroxyapatite, acalcium compound, which is part of the mineral matrix of bone. Bindingto the site allows the drug to be taken up by mature osteoclasts duringthe resorption process, and to act intracellularly as an isoprenoiddiphosphate lipid analogue, disrupting the farnesylation andgeranylgeranylation of small GTPase signaling proteins and potentiatingselective osteoclast apoptosis. Clinical studies indicate thatbisphosphonates increase bone mineral density (BMD) of the existingskeleton and reduce the risk of spine fractures for postmenopausal womenwith osteoporosis. In postmenopausal women with very severeosteoporosis, bisphosphonates reduce the risk of fractures throughoutthe skeleton.

Ibandronate is disclosed in U.S. Pat. No. 4,927,814, which disclosure isincorporated herein by reference. Ibandronate may be represented by thefollowing formula:

Ibandronate is commercialized as the sodium salt,3-(N-methyl-N-pentyl)amino -1-hydroxypropane-1,1-diphosphonic acid,monosodium salt, monohydrate (Boniva®). Ibandronate has the molecularformula C₉H₂₂NO₇P₂Na.H₂O and a molecular weight of 359.24. Ibandronatesodium is a white- to off-white powder, which is freely soluble in waterand practically insoluble in organic solvents.

The modified amino acid carriers in the present invention may beselected from a wide variety of modified amino acids, andpharmaceutically acceptable salts thereof. The modified amino acids arepreferably ω-amino acids modified by acylation or sulfonation of theamino group, particularly with phenyl or cyclohexyl groups. The phenylor cyclohexyl groups may contain a variety of substituents such ashydroxy, methyl, fluoro, and chloro. Modified amino acid carriers usefulin the present invention are disclosed in U.S. Pat. Nos. 5,650,386,5,866,536, 5,965,121, 5,989,539, 6,001,347, 6,344,213, 6,346,242,6,623,731, and 6,699,467, which disclosures are incorporated herein byreference.

The modified amino acids of the present invention are preferablyrepresented by formula (1):HOOC—R₁—N(R₂)—X—R₃   (1)In formula (1):

X is CO or SO₂; preferably X is CO.

R₁ is selected from the group consisting of C₃-C₂₄ alkyl, C₂-C₂₀alkenyl, C₂-C₂₀ alkyne, C₅-C₆ cycloalkyl, phenyl, and naphthyl;preferably R₁ is C₃-C₁₁ alkyl; more preferably R₁ is C₃-C₉ alkyl; andmost preferably R₁ is C₇-C₉ alkyl.

R₂ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, andC₂-C₄ alkenyl; preferably R₂ is hydrogen or C₁-C₄ alkyl; more preferablyR₂ is hydrogen or C₁-C₂ alkyl; and most preferably R₂ is hydrogen.

R₃ is selected from the group consisting of C₁-C₇ alkyl, C₃-C₁₀cycloalkyl, phenyl, thienyl, pyrrolyl, and pyridinyl; wherein R₃ may besubstituted by substituents selected from the group consisting of C₁-C₅alkyls, C₂-C₄ alkenyls, F, Cl, OH, SO₂, COOH, and SO₃H. Preferably, R₃is 2-hydroxyphenyl.

A preferred modified amino acid carrier in the present invention issodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC), which is disclosedin U.S. Pat. No. 5,650,386, which disclosure is incorporated herein byreference. N-(8-(2-hydroxybenzoyl)amino)caprylate has the structure setout below.

Another preferred modified amino acid carrier isN-(10-(2-hydroxybenzoyl) amino)capricate, which is disclosed in U.S.Pat. Nos. 5,866,536 and 6,344,213, which disclosures are incorporatedherein by reference. N-(10-(2-hydroxybenzoyl)amino)capricate has thestructure set out below.

Another preferred modified amino acid carrier isN-(2-methoxybenzoyl)-3-(4-aminophenyl)proprionate, which is disclosed inU.S. Pat. No. 5,965,121, which disclosure is incorporated herein byreference. N-(2-methoxybenzoyl)-3-(4-aminophenyl)proprionate has thestructure set out below.

Another preferred modified amino acid carrier isN-(3-dimethylaminobenzoyl)-3-(4-aminophenyl)butyrate, which is disclosedin U.S. Pat. No. 5,989,539, which disclosure is incorporated herein byreference. N-(3-dimethylaminobenzoyl)-3-(4-aminophenyl)butyrate has thestructure set out below.

Another preferred modified amino acid carrier isN-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate, which is disclosed inU.S. Pat. No. 6,001,347, which disclosure is incorporated herein byreference. N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate has thestructure set out below.

Another preferred modified amino acid carrier isN-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate, which is disclosed in U.S.Pat. No. 6,346,242, which disclosure is incorporated herein byreference. N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate has thestructure set out below.

Another preferred modified amino acid carrier isN-(4-(3-cyclohexyl-propionyl)amino)butyrate, which is disclosed in U.S.Pat. No. 6,623,731, which disclosure is incorporated herein byreference. N-(4-(3-cyclohexyl-propionyl)amino)butyrate has the structureset out below.

Another preferred modified amino acid carrier isN-(6-(4-methylcyclohexyl-carbonyl)amino)caproate, which is disclosed inU.S. Pat. No. 6,699,467, which disclosure is incorporated herein byreference. N-(6-(4-methylcyclohexyl-carbonyl)amino)caproate has thestructure set out below.

The most preferred modified amino acid carrier is sodiumN-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).

The ratio of bisphosphonate to modified amino acid carrier is such thatabsorption of the orally administered bisphosphonate in thegastrointestinal tract is facilitated over that of absorption of thebisphosphonate when orally administered alone. The ratio ofbisphosphonate to modified amino acid carrier according to the presentinvention may vary within limits. The ratio of bisphosphonate tomodified amino acid carrier may be adjusted to the individualrequirements in each particular case including the particularbisphosphonate being administered, the particular modified amino acidcarrier being employed, the condition being treated, as well as thepatient being treated. The ratio of bisphosphonate to modified aminoacid carrier is preferably such that absorption of the orallyadministered bisphosphonate in the gastrointestinal tract is at least 2times, preferably 3 times, more preferably 4 times, and most preferably5 times greater than that of the bisphosphonate when orally administeredalone. In general, in the case of oral administration to adult humansweighing approximately 70 Kg, the ratio of bisphosphonate to modifiedamino acid carrier, as measured by weight of each compound as the freeacid in the pharmaceutical composition, is from about 1:30 to about 1:1,preferably about 1:20, more preferably about 1:10, and most preferablyabout 1:5, respectively.

The therapeutically effective amount or dosage of bisphosphonateaccording to this invention can vary within wide limits. Such dosagewill be adjusted to the individual requirements in each particular caseincluding the condition being treated, the patient being treated, aswell as the specific bisphosphonate being administered.

For example, the recommended oral dose of ibandronate for the treatmentof osteoporosis, when administered alone, to adult humans weighingapproximately 70 Kg is 2.5 mg once daily, or 150 mg once monthly. In thepresent invention, the daily dose of ibandronate for the treatment ofosteoporosis, when administered with a modified amino acid carrier, islowered to from about 1.25 mg to about 0.25 mg, preferably from about 1mg to about 0.4 mg, more preferably from about 0.65 mg to about 0.5 mg,and most preferably about 0.5 mg. The monthly dose of ibandronate forthe treatment of osteoporosis, when administered with a modified aminoacid carrier, is lowered to from about 75 mg to about 15 mg, preferablyfrom about 60 mg to about 25 mg, more preferably from about 40 mg toabout 30 mg, and most preferably about 30 mg.

The recommended oral dose of ibandronate for the treatment ofhypercalcemia of cancer or the treatment of metastatic bone pain, whenadministered alone, to adult humans weighing approximately 70 Kg is 50mg once daily. In the present invention, the daily dose of ibandronatefor the treatment of hypercalcemia of cancer or the treatment ofmetastatic bone pain, when administered with a modified amino acidcarrier, is lowered to from about 25 mg to about 5 mg, preferably fromabout 20 mg to about 8 mg, more preferably from about 13 mg to about 10mg, and most preferably about 10 mg.

The anticipated oral dose of ibandronate for the treatment ofhypercalcemia of cancer or the treatment of metastatic bone pain, whenadministered alone, to adult humans weighing approximately 70 Kg is 350mg weekly. In the present invention, the anticipated weekly dose ofibandronate for the treatment of hypercalcemia of cancer or thetreatment of metastatic bone pain, when administered with a modifiedamino acid carrier, is expected to be lowered to from about 175 mg toabout 35 mg, preferably from about 140 mg to about 56 mg, morepreferably from about 90 mg to about 70 mg, and most preferably about 70mg.

The pharmaceutical dosage forms of the present invention may be preparedby simply admixing the bisphosphonate with the modified amino acidcarrier prior to administration. The dosage forms may also be preparedby admixing an aqueous solution of the bisphosphonate with the modifiedamino acid carrier, just prior to administration. The solutions mayoptionally contain additives such as lactose monohydrate, croscarmellosesodium, povidone, water, sodium stearyl fumarate, and the like.Preferably, the solid pharmaceutical dosage form is prepared byintimately contacting the bisphosphonate with the modified amino acidcarrier.

The dosage forms are preferably in tablet or capsule form. In oneembodiment, the dosage form is a tablet and includes povidone. Inanother embodiment, the dosage form is a capsule and includes povidone.Povidone is preferably present in the dosage form in an amount fromabout 2% to about 30%, preferably from about 10% to about 20%, mostpreferably from about 12% to about 15%, by weight of the totalcomposition.

The modified amino acid carriers may also be used to form microspherescontaining the bisphosphonate. Microspheres are particularly useful forthe oral administration of active agents, which do not pass, or onlyfractionally pass, through the gastrointestinal tract or are susceptibleto chemical or enzymatic cleavage in the gastrointestinal tract. Methodsfor preparing microspheres are known and are disclosed, for example, inU.S. Pat. No. 5,650,386, which disclosure is incorporated herein byreference.

In another embodiment, the present invention provides a method fortreating osteoporosis comprising orally administering to a subject, inneed thereof, the novel solid pharmaceutical dosage form of the presentinvention. In yet another embodiment, the present invention provides amethod for treating hypercalcemia of cancer comprising orallyadministering to a subject, in need thereof, the novel solidpharmaceutical dosage form of the present invention. In still yetanother embodiment, the present invention provides a method for treatingmetastatic bone pain comprising orally administering to a subject, inneed thereof, the novel solid pharmaceutical dosage form of the presentinvention.

In still yet another embodiment, the present invention provides a methodfor preparing a solid pharmaceutical dosage form for oral administrationcomprising admixing:

(a) a bisphosphonate, or a pharmaceutically acceptable salt thereof,which bisphosphonate is present in an amount not therapeuticallyeffective when the bisphosphonate is orally administered alone; and

(b) a modified amino acid carrier, or a pharmaceutically acceptable saltthereof, which modified amino acid carrier is present in an amounteffective to facilitate absorption of the bisphosphonate in thegastrointestinal tract such that the bisphosphonate is therapeuticallyeffective;

wherein the ratio of bisphosphonate to modified amino acid carrier isfrom about 1:30 to about 1:1, respectively.

In a preferred embodiment, the present invention provides an improvedmethod for preparing the solid pharmaceutical dosage forms of thepresent invention. The method comprises providing the solidpharmaceutical dosage form wherein the bisphosphonate is in intimatecontact with the modified amino acid carrier. Intimate contact is aclose physical association between the bisphosphonate with the modifiedamino acid carrier and may be achieved by preparing the dosage form bygranulation, spray drying, fluid bed coating, fluid bed layering, andthe like.

The pharmaceutical dosage forms of the present invention can be preparedaccording to the examples set out below. The examples are presented forpurposes of demonstrating, but not limiting, the preparation of thecompounds and compositions of this invention.

EXAMPLES

In accordance with the present invention, the following examples areprovided to illustrate solid pharmaceutical dosage forms, which utilizedifferent ratios of bisphosphonate to modified amino acid carrier.

Example 1

In this example, 30 mg film coated ibandronic acid tablets were preparedwherein the ratio of ibandronic acid to sodiumN-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) was 1:5. FormulationComposition Item # Ingredient mg per Tablet Kernel Composition 1.Ibandronate Monosodium Salt Monohydrate 33.75¹ 2. SodiumN-[8-(2-hydroxybenzoyl)amino]caprylate 161.81² 3. Lactose Monohydrate(Pharmatose ® 350) 17.50 4. Croscarmellose Sodium (Ac-Di-Sol ®) 13.44 5.Polyvinylpyrrolidone (Povidone; PVP K30) 30.50 6. Purified Water³ q.s.7. Croscarmellose Sodium (Ac-Di-Sol ®) (External) 9.25 8. Sodium StearylFumarate (External) 3.75 Total Weight of Kernel 270.00 CoatingComposition 9. Opadry White YS-1-7002 05.50 10. Purified Water³ q.s.Total Weight of Film Coated Tablet 275.50¹Equivalent to 30 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Pharmatose ® 350 isreduced to compensate for the increase in ibandronic acid.²Equivalent to 150 mg SNAC (anhydrous free acid).³Removed during processing.MethodKernel Preparation Procedure

About 50% of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) wasplaced in a PK blender or equivalent (Bin or Bohle mixer). Ibandronatemonosodium salt monohydrate was then added to the mixture followed bythe remainder of the SNAC. Pharmatose® 350, Ac-Di-Sol®, and PVP K30 werethen added and the mixture was mixed for 15 minutes. The MFB-mini-fluidbed processor was set at the top spray set-up mode. The powder mix wasthen transferred into a MFB-mini-fluid bed processor. Fluidization wasbegun and the processor was pre-heated to 55° C. and the atomizationpressure was set to less than 1 bar. The granulation process was startedwith the peristaltic pump using purified water as the granulatingliquid. An initial amount equivalent to 20% w/w of the powder load wasused and added over a period of 50±10 minutes. The inlet temperature wasset to 55° C. with a range of 50° C.-60° C. Additional water may beadded if necessary to achieve a consistent granulation. The peristalticpump was then turned off to stop the granulation process. Thegranulation was then dried setting the inlet temperature at 60° C. witha range of 55° C.-65° C. Drying was continued until the moisture contentwas less than 1.5%. The dried granulation was milled using a FitzMillwith screen # 2, knives forward at medium speed. Sodium stearyl fumaratewas prescreened through a # 30 mesh and the weight of the milledgranulation was recorded and the weights of the external ingredientswere adjusted: croscarmellose sodium (Ac-Di-Sol®) and the prescreenedsodium stearyl fumarate. The milled granulation was transferred into aPK blender or equivalent and the adjusted amount of croscarmellosesodium (Ac-Di-Sol®) was added and the mixture was mixed for 20 minutes.About 50% of the mixed granulation was removed. The prescreened sodiumstearyl fumarate was added to the remaining mixed granulation in the PKblender. The remainder of the mixed granulation was added and themixture was mixed for 5 minutes. The final blend was compressed intokernels at a 270 mg weight (range of 260-280 mg). The kernels werestored in a tightly closed double polyethylene-lined container with 2silica gel packets between the polyethylene bags. Physical ProductSpecifications of The Kernel Tablet Tooling: plain oval size 0.4865″ ×0.257″ Tablet Weight (Target) 270 mg Tablet Weight (Range) 260-280 mgTablet Thickness (Target) 4.5 mm Tablet Thickness (Range) 4.0-5.0 mmTablet Hardness (Target) 10 scu Tablet Hardness (Range) 8-15 scuDisintegration Time (0.01 N HCl) <20 minutes Friability <1.0%Film Coating Procedure

A film coating suspension was prepared having the following composition:Film Coating Suspension Ingredient % w/w Opadry White YS-1-7002 8.00Purified Water q.s. 100.00

In a stainless steel container, opadry white in purified water wasdispersed by mixing gently (to avoid air entrapment) for 45 minutes witha Lightnin Mixer (300 rpm), until completely dispersed. The kernels wereplaced into a perforated coating pan and heated with warm inlet air of45° C.±5° C. with intermittent jogging until the exhaust air temperaturereached 40° C.±5° C. The inlet temperature was increased to 60° C.±5° C.and the kernels were coated with the coating suspension, stirredcontinuously, using an air spray system and maintaining the exhaust airtemperature at 40° C.±5° C. A quantity of 5.5 mg of the film coat wasapplied on a dry basis, per tablet. The coated tablets were dried, withan inlet air temperature of 40° C.±5° C., by jogging until the moisturecontent of the tablets, determined by a Moisture Analyzer at 90° C., wasless than 3%. The heat was then turned off and the tablets were cooledto room temperature by occasional jogging. The tablets were stored in atightly closed double polyethylene-lined container with 2 silica gelpackets between the polyethylene bags.

Example 2

In this example, 30 mg film coated ibandronic acid tablets were preparedwherein the ratio of ibandronic acid to sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) was 1:10. Formulation Composition Item #Ingredient mg per Tablet Kernel Composition 1. Ibandronate MonosodiumSalt Monohydrate 33.75¹ 2. Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate323.63² 3. Lactose Monohydrate (Pharmatose ® 350) 35.00 4.Croscarmellose Sodium (Ac-Di-Sol ®) 25.62 5. Polyvinylpyrrolidone(Povidone; PVP K30) 61.00 6. Purified Water³ q.s. 7. CroscarmelloseSodium (Ac-Di-Sol ®) (External) 18.50 8. Sodium Stearyl Fumarate(External) 7.50 Total Weight of Kernel 505.00 Coating Composition 9.Opadry White YS-1-7002 10.50 10. Purified Water³ q.s. Total Weight ofFilm Coated Tablet 515.50¹Equivalent to 30 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Pharmatose ® 350 isreduced to compensate for the increase in ibandronic acid.²Equivalent to 300 mg SNAC (anhydrous free acid).³Removed during processing.

The method for preparing the kernel is similar to that set out inExample 1. Physical Product Specifications of The Kernel Tablet Tooling:plain oval size 0.2945″ × 0.558″ Tablet Weight (Target): 505 mg TabletWeight (Range): 490-520 mg Tablet Thickness (Target): 6.00 mm TabletThickness (Range): 5.5-6.5 mm Tablet Hardness (Target): 15 scu TabletHardness (Range): 10-20 scu Disintegration Time (0.01 N HCl): <20minutes Friability: <1.0%Film Coating Procedure

A film coating suspension was prepared having the following composition:Film Coating Suspension Ingredient % w/w Opadry White YS-1-7002 8.00Purified Water q.s. 100.00

The film coating suspension was prepared in a manner similar to that setout in Example 1.

Example 3

In this example, 30 mg film coated ibandronic acid tablets were preparedwherein the ratio of ibandronic acid to sodiumN-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC) was 1:20. FormulationComposition Item # Ingredient mg per Tablet Kernel Composition 1.Ibandronate Monosodium Salt Monohydrate 33.75¹ 2. SodiumN-[8-(2-hydroxybenzoyl)amino]caprylate 647.25² 3. Lactose Monohydrate(Pharmatose ® 350) 70.00 4. Croscarmellose Sodium (Ac-Di-Sol ®) 50.00 5.Polyvinylpyrrolidone (Povidone; PVP K30) 122.00 6. Purified Water³ q.s.7. Croscarmellose Sodium (Ac-Di-Sol ®) (External) 37.00 8. SodiumStearyl Fumarate (External) 15.00 Total Weight of Kernel 975.00 CoatingComposition 9. Opadry White YS-1-7002 20.00 10. Purified Water³ q.s.Total Weight of Film Coated Tablet 995.00¹Equivalent to 30 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Pharmatose ® 350 isreduced to compensate for the increase in ibandronic acid.²Equivalent to 600 mg SNAC (anhydrous free acid).³Removed during processing.

The method for preparing the kernel is similar to that set out inExample 1. Physical Product Specifications of The Kernel Tablet Tooling:plain oval size 0.827″ × 0.317″ Tablet Weight (Target): 975 mg TabletWeight (Range): 945-1005 mg Tablet Thickness (Target): 7.00 mm TabletThickness (Range): 6.5-7.5 mm Tablet Hardness (Target): 20 scu TabletHardness (Range): 15-25 scu Disintegration Time (0.01 N HCl): <20minutes Friability: <1.0%Film Coating Procedure

A film coating suspension was prepared having the following composition:Film Coating Suspension Ingredient % w/w Opadry White YS-1-7002 8.00Purified Water q.s. 100.000

The film coating suspension was prepared in a manner similar to that setout in Example 1.

Example 4

In this example, 30 mg film coated ibandronic acid tablets were preparedwherein the ratio of ibandronic acid to sodiumN-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC) was 1:5. FormulationComposition Item # Ingredient mg per Tablet Kernel Composition 1.Ibandronate Monosodium Salt Monohydrate 33.75¹ 2. SodiumN-[8-(2-hydroxybenzoyl)amino]caprylate 161.81² 3. Lactose Monohydrate(Pharmatose ® 350) 17.50 4. Croscarmellose Sodium (Ac-Di-Sol ®) 13.44 5.Polyvinylpyrrolidone (Povidone; PVP K30) 30.50 6. Purified Water³ q.s.7. Croscarmellose Sodium (Ac-Di-Sol ®) (External) 9.25 8. Sodium StearylFumarate (External) 3.75 Total Weight of Kernel 270.00 CoatingComposition 9. Opadry White YS-1-7002 5.50 10. Purified Water³ q.s.Total Weight of Film Coated Tablet 275.50¹Equivalent to 30 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Pharmatose ® 350 isreduced to compensate for the increase in ibandronic acid.²Equivalent to 150 mg SNAC (anhydrous free acid).³Removed during processing.

Using a propeller mixer or a homogenizer-mixer set at slow speed,ibandronate monosodium salt monohydrate was dissolved in purified waterto form a 33% w/w solution (warm at 45° C. ranges 40 to 50° C., ifnecessary to help dissolving the drug). The drug was added in smallportions while maintaining a slow speed during mixing to avoid foamformation. Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) wasplaced in a PK blender or equivalent (Bin or Bohle mixer). Pharmatose®350, Ac-Di-Sol®, and PVP K30 were then added and mixed for 20 minutes.The MFB-mini-fluid bed processor was set at the Top Spray set-up mode.The powder mix was transferred into the MFB-mini-fluid bed processor.The process of fluidization was started and the processor pre-heated ata temperature of 50° C. The atomization pressure was set to less than 1bar. With the peristaltic pump set at a slow speed, the granulationprocess was started using the solution of the drug in purified water asthe granulating liquid. The solution was added over a period of 45minutes (range 30-60 minutes). The inlet temperature was targeted to 50°C., with a range of 45 to 55° C. Additional water was added if necessaryto achieve a consistent granulation. The granulation process was stoppedby turning off the peristaltic pump. The granulation was started settingthe inlet temperature range at 55-60° C. Drying was continued until themoisture content (loss on drying), as measured by moisture analyzer setat 90° C., was less than 1.5%. The dried granulation was milled using aFitzMill with screen # 2, knives forward at medium speed. Sodium stearylfumarate was prescreened through # 30 mesh. The weight of the milledgranulation was recorded and the weight of the external ingredients wasadjusted: Croscarmellose Sodium Ac-Di-Sol® and the prescreened Sodiumstearyl fumarate. The milled granulation was transferred into a PKblender or equivalent. The adjusted amount of Croscarmellose Sodium(Ac-Di-Sol®) was added and mixed for 20 minutes. About 50% of the mixedgranulation was removed. The prescreened Sodium Stearyl Fumarate wasadded to the remaining mixed granulation in the PK blender. Theremaining portion of the mixed granulation removed was added and mixedfor 5 minutes. The final blend was compressed into kernels at 270 mgweight (range of 260-280 mg). The kernels were stored in a tightlyclosed polyethylene-lined container with 2 silica gel packets betweenthe polyethylene bags. Physical Product Specifications of The KernelTablet Tooling: plain oval size 0.4865″ × 0.257″ Tablet Weight (Target)270 mg Tablet Weight (Range) 260-280 mg Tablet Thickness (Target) 4.5 mmTablet Thickness (Range) 4.0-5.0 mm Tablet Hardness (Target) 10 scuTablet Hardness (Range) 8-15 scu Disintegration Time (0.01 N HCl) <20minutes Friability <1.0%Film Coating Procedure

A film coating suspension was prepared having the following composition:Film Coating Suspension Ingredient % w/w Opadry White YS-1-7002 8.00Purified Water q.s. 100.00

In a stainless steel container, opadry white in purified water wasdispersed by mixing (gently to avoid air entrapment) for 45 minutes witha Lightnin Mixer (300 rpm), until completely dispersed. The kernels wereplaced into a perforated coating pan and heated with warm inlet air of45° C.±5° C. with intermittent jogging until the exhaust air temperaturereached 40° C.±5° C. The inlet temperature was increased to 60° C.±5° C.and the kernels were coated with the coating suspension, stirredcontinuously, using an air spray system and maintaining the exhaust airtemperature at 40° C.±5° C. A quantity of 5.5 mg of the film coat wasapplied on a dry basis, per tablet. The coated tablets were dried, withan inlet air temperature of 40° C.±5° C., by jogging until the moisturecontent of the tablets, determined by a Moisture Analyzer at 90° C., wasless than 3%. The heat was then turned off and the tablets were cooledto room temperature by occasional jogging. The tablets were stored in atightly closed double polyethylene-lined container with 2 silica gelpackets between the polyethylene bags.

Example 5

In this example, 30 mg film coated ibandronic acid tablets were preparedwherein the ratio of ibandronic acid to sodiumN-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC) was 1:10. FormulationComposition mg per Item # Ingredient Tablet Kernel Composition 1.Ibandronate Monosodium Salt Monohydrate 33.75¹ 2. SodiumN-[8-(2-hydroxybenzoyl)amino]caprylate 323.63² 3. Lactose Monohydrate(Pharmatose ® 350) 35.00 4. Croscarmellose Sodium (Ac-Di-Sol ®) 25.62 5.Polyvinylpyrrolidone (Povidone; PVP K30) 61.00 6. Purified Water³ q.s.7. Croscarmellose Sodium (Ac-Di-Sol ®) (External) 18.50 8. SodiumStearyl Fumarate (External) 7.50 Total Weight of Kernel 505.00 CoatingComposition 9. Opadry White YS-1-7002 10.50 10. Purified Water³ q.s.Total Weight of Film Coated Tablet 515.50¹Equivalent to 30 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Pharmatose ® 350 isreduced to compensate for the increase in ibandronic acid.²Equivalent to 300 mg SNAC (anhydrous free acid).³Removed during processing.

The method for preparing the kernel is similar to that set out inExample 4. Physical Product Specifications of The Kernel Tablet Tooling:plain oblong size 0.33″ × 0.625″ Tablet Weight (Target): 505 mg TabletWeight (Range): 490-520 mg Tablet Thickness (Target): 6.00 mm TabletThickness (Range): 5.5-6.5 mm Tablet Hardness (Target): 12 scu TabletHardness (Range): 10-15 scu Disintegration Time (0.01 N HCl): <20minutes Friability: <1.0%

A film coating suspension was prepared having the following composition:Film Coating Suspension Ingredient % w/w Opadry White YS-1-7002 8.00Purified Water q.s. 100.00

The film coating suspension was prepared in a manner similar to that setout in Example 4.

Example 6

In this example, 30 mg film coated ibandronic acid tablets were preparedwherein the ratio of ibandronic acid to sodiumN-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) was 1:20. FormulationComposition mg per Item # Ingredient Tablet Kernel Composition 1.Ibandronate Monosodium Salt Monohydrate 33.75¹ 2. SodiumN-[8-(2-hydroxybenzoyl)amino]caprylate 647.25² 3. Lactose Monohydrate(Pharmatose ® 350) 70.00 4. Croscarmellose Sodium (Ac-Di-Sol ®) 50.00 5.Polyvinylpyrrolidone (Povidone; PVP K30) 122.00 6. Purified Water³ q.s.7. Croscarmellose Sodium (Ac-Di-Sol ®) (External) 37.00 8. SodiumStearyl Fumarate (External) 15.00 Total Weight of Kernel 975.00 CoatingComposition 9. Opadry White YS-1-7002 20.00 10. Purified Water³ q.s.Total Weight of Film Coated Tablet 995.00¹Equivalent to 30 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Pharmatose ® 350 isreduced to compensate for the increase in ibandronic acid.²Equivalent to 600 mg SNAC (anhydrous free acid).³Removed during processing.

The method for preparing the kernel is similar to that set out inExample 4. Physical Product Specifications of The Kernel Tablet Tooling:plain oval size 0.827″ × 0.317″ Tablet Weight (Target): 975 mg TabletWeight (Range): 945-1005 mg Tablet Thickness (Target): 7.00 mm TabletThickness (Range): 6.5-7.5 mm Tablet Hardness (Target): 16 scu TabletHardness (Range): 13-25 scu Disintegration Time (0.01 N HCl): <30minutes Friability: <1.0%Film Coating Procedure

A film coating suspension was prepared having the following composition:Film Coating Suspension Ingredient % w/w Opadry White YS-1-7022 8.00Purified Water q.s. 100.000

The film coating suspension was prepared in a manner similar to that setout in Example 4.

Example 7

In this example, 30 mg ibandronic acid capsules were prepared whereinthe ratio of ibandronic acid to sodiumN-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) was 1:5. FormulationComposition mg per Item # Ingredient Capsule Drug Layering 1.Ibandronate Monosodium Salt Monohydrate¹ 33.750² 2. SodiumN-[8-(2-hydroxybenzoyl)amino]caprylate 161.810³ 3. Kollidon ® 12PF(povidone) 9.780 4. Altalc 500 9.780 5. Cellets 200 (microcrystallinecellulose) 53.780 6. Purified Water (501.950)⁴ Seal Coat 7. Kollidon ®12PF (povidone) 0.135 8 Zeopharm 600 2.565 9. Purified Water (51.300)⁴Capsule Fill Weight 271.600 Encapsulation 10. White Opaque Hard GelatinCapsule #2 61.00⁵ Total Weight of Capsule 332.600¹Fine Powder.²Equivalent to 30 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Cellets 200 is reduced tocompensate for the increase in ibandronic acid.³Equivalent to 150 mg SNAC (anhydrous free acid).⁴Removed during processing.⁵Target capsule weight.MethodDrug Layering ProcedurePreparation of the Drug Layering Suspension

In a stainless steel container, Kollidon 12 PF was added to purifiedwater while mixing using a propeller mixer at medium speed. Mixing wascontinued until the Kollidon 12 PF was completely dissolved. IbandronateMonosodium Salt Monohydrate was added to the solution while mixing atmedium speed. Mixing was continued until the drug was completelydissolved. SNAC was added to the solution while mixing at medium speed.Mixing was continued for at least 1 hour or until a uniform dispersionwas obtained. The suspension was then transported in tightly closedcontainers to Glatt Air Techniques. Altalc 500 was added to thesuspension while mixing using a propeller mixer at medium speed. Mixingwas continued for at least 1 hour or until a uniform dispersion wasobtained. A portion (approximately 2-liters) of the coating suspensionwas warmed in a jacketed vessel equilibrated at 50°±5° C., while mixingusing a propeller mixer at medium speed. The remainder of the suspensionwas mixed using a propeller mixer at medium speed.

Application of the Drug Layering Suspension

The quantity of Cellets 200 was placed into a fluid bed coater with aWurster HS insert. The Cellets 200 was warmed for at least 2 minuteswith inlet air temperature of 70°±10° C., providing sufficient airvolume to fluidize the Cellets 200. The warm drug layering suspensionwas sprayed, with continuous mixing using a propeller mixer at mediumspeed, to the Cellets 200 using the following processing conditions:Inlet temperature 70° ± 10° C. Target product temperature 50° C. (Range:35°-55° C.) Nozzle orifice 1.2 mm Atomization air pressure 3.0 ± 1.0 BarPartition Height: 20 mmThe air volume used to fluidize the Cellets 200 was recorded.

The drug layering suspension was re-supplied to maintain its volume(approximately 2-liters) throughout the coating process by pumping thecoating suspension at the rate comparable to the coating spray rate. Aquantity of 215.120 mg per capsule (on a dry basis) of the drug layeringsuspension was applied per 53.780 mg per capsule of the Cellets 200.

Seal Coating Procedure

Preparation of the Seal Coating Suspension

In a stainless steel container, Kollidon 12 PF was added to purifiedwater while mixing using a propeller mixer at medium speed. Mixing wascontinued until the Kollidon 12 PF was completely dissolved. Thesolution was transported in a tightly closed container to Glatt AirTechniques. Zeopharm 600 was added to the solution while mixing using apropeller mixer at medium speed for at least 30 minutes or until auniform dispersion was obtained.

Application of the Seal Coating Suspension

The seal coating suspension was sprayed, with continuous mixing using apropeller mixer at medium speed, to the drug layered beadlets using thefollowing processing conditions: Inlet temperature 60° ± 10° C. Targetproduct temperature 40° C. (Range: 30°-50° C.) Nozzle orifice 1.2 mmAtomization air pressure 3.0 ± 1.0 Bar Partition Height: 20 mmThe air volume used to fluidize the beadlets was recorded.

A quantity of 2.7 mg per capsule (on a dry basis) of the seal coat wasapplied per 268.9 mg per capsule of the drug layered beadlets.

The seal coated beadlets were dried using an inlet air temperature of60°±10° C. until the moisture content of the beadlets, determined by theKarl Fisher Method, was less than 2% w/w. The beadlets were cooled toobtain a product temperature of 40°±5° C. by turning off process airheat. The beadlets were discharged into a double polyethylene linedfiber drum. The finished beadlets were shipped in double polyethylenebags in a closed fiber drum with two silica gel bags between thepolyethylene bags at 25° C. (77° F.) for encapsulation.

Encapsulation

Using a capsule filling machine, the beadlets were filled into whiteopaque hard gelatin capsules, size #2, at a target weight of 271.6mg/capsule (Range: 258.0-285.2 mg/capsule). The finished capsules werestored in double polyethylene bags in a closed fiber drum with twosilica gel bags between the polyethylene bags at 25° C. (range permittedto 15°-30° C.).

Example 8

In this example, 30 mg ibandronic acid capsules were prepared whereinthe ratio of ibandronic acid to sodiumN-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) was 1:10. FormulationComposition Item # Ingredient mg per Capsule Drug Layering 1.Ibandronate Monosodium Salt Monohydrate¹ 33.750² 2. SodiumN-[8-(2-hydroxybenzoyl)amino]caprylate 323.630³ 3. Kollidon ® 12PF(povidone) 17.870 4. Altalc 500 17.870 5. Cellets 200 (microcrystallinecellulose) 98.280 6. Purified Water (917.260)⁴ Seal Coat 7. Kollidon ®12PF (povidone) 0.250 8 Zeopharm 600 4.650 9. Purified Water (93.480)⁴Capsule Fill Weight 496.300 Encapsulation 10. White Opaque Hard GelatinCapsule #0 96.00⁵ Total Weight of Capsule 592.300¹Fine Powder.²Equivalent to 30 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Cellets 200 is reduced tocompensate for the increase in ibandronic acid.³Equivalent to 300 mg SNAC (anhydrous free acid).⁴Removed during processing.⁵Target capsule weight.

The capsule forming procedure was prepared in a manner similar to thatset out in Example 7.

Example 9

In this example, 15 mg ibandronic acid capsules were prepared whereinthe ratio of ibandronic acid to sodiumN-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) was 1:20. FormulationComposition Item # Ingredient mg per Capsule Drug Layering 1.Ibandronate Monosodium Salt Monohydrate¹ 16.875² 2. SodiumN-[8-(2-hydroxybenzoyl)amino]caprylate 323.630³ 3. Kollidon ® 12PF(povidone) 17.025 4. Altalc 500 17.025 5. Cellets 200 (microcrystallinecellulose) 93.640 6. Purified Water (873.962)⁴ Seal Coat 7. Kollidon ®12PF (povidone) 0.234 8 Zeopharm 600 4.446 9. Purified Water (88.920)⁴Capsule Fill Weight 472.875 Encapsulation 10. White Opaque Hard GelatinCapsule #0 96.00⁵ Total Weight of Capsule 568.875¹Fine Powder.²Equivalent to 15 mg of anhydrous ibandronic acid. The quantity ofibandronic acid is to be adjusted if the assay is less than 100%. If theassay adjustment is required, the quantity of Cellets 200 is reduced tocompensate for the increase in ibandronic acid.³Equivalent to 300 mg SNAC (anhydrous free acid).⁴Removed during processing.⁵Target capsule weight.

The capsule forming procedure was prepared in a manner similar to thatset out in Example 7.

Example 10

In this example, 30 mg hard gelatin capsules are made using a powdermixture of SNAC and ibandronate. FORMULATION COMPOSITION Item # mg percapsule 1. Ibandronate Monosodium Salt Monohydrate¹ 33.75² 2. SodiumN-[8-(2- 161.81³ hydroxybenzoyl)amino]caprylate (SNAC) 3. CroscarmelloseSodium (Ac-Di-Sol) 1.50 4. Polyvinylpyrrolidone (Povidone; PVP K30)12.14 5. Purified Water Qs.ad.⁴ 6. Calcium Silicate (Zeopharm 600)(External) 2.00 7. Croscarmellose Sodium (Ac-Di-Sol) (External) 1.50 8.Sodium Stearyl Fumarate 4.30 Total Weight of Capsule Fill 217.00 9.White Opaque Hard Gelatin Capsule #1¹Fine powder²Equivalent to 30 mg anhydrous Ibandronic Acid. The quantity ofibandronate sodium is to be adjusted if the assay is less than 100%. Ifthe assay adjustment is required, the quantity of PVP K30 is reduced tocompensate for the increase in ibandronate sodium.³Equivalent to 150 mg SNAC (anhydrous free acid)⁴Removed during processing

About 50% of the total quantity of Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) (item 2) is placed in a mixer, such as a PKblender or the equivalent (Bin or Bohle mixer). Ibandronate sodium (item1), the remainder of SNAC, Ac-Di-Sol (item 3), and PVP K30 (item 4) areadded and the components are mixed for 15 minutes to yield a powder mix.A MP ⅔ fluid bed processor at the Top Spray mode is set up. The powdermix is transferred into the MP ⅔ fluid bed processor. The process offluidization is started and the processor is pre-heated to a temperatureof 55° C. The atomization pressure is set to less than 1 bar. Using aperistaltic pump, the granulation process is started using PurifiedWater as the granulating liquid, using an initial amount equivalent to30% w/w of the powder load and added over a period of 45±15 minutes. Aninlet temperature target of 60° C. with a range of 55° to 65° C. is set.Additional water is added as necessary to achieve a consistentgranulation.

The granulation process is stopped by turning off the peristaltic pump.The granulation is dried by setting the inlet temperature at 65° C. witha range of 65° to 70° C., and is continued until the moisture content(loss on drying), as measured by a moisture analyzer set at 90° C., isless than 1.5%. The dried granulation is milled using a Comill withscreen # 055R, at a speed of 1500 rpm (range 1400 rpm to 1800 rpm), toyield a milled granulation. Zeopharm (item 6) and sodium stearylfumarate (item 8) are separately screened through a #40 mesh screen. Theweight of the milled granulation is recorded and the weights of theZeopharm (item # 6), Croscarmellose Sodium (Ac-Di-Sol) (item 7) andSodium Stearyl Fumarate (item 8) are adjusted to their correctproportions. The milled granulation is transferred into a PK blender orequivalent. The adjusted amounts of prescreened Zeopharm andCroscarmellose Sodium (Ac-Di-Sol) are added and mixed for 20 minutes toyield a mixed granulation, and then about 50% of the mixed granulationis removed. The prescreened Sodium Stearyl Fumarate is added to theremaining 50% of the mixed granulation in the PK blender, followed bythe addition of the portion of the mixed granulation previously removed,followed by mixing for 5 minutes to yield a final blend. This finalblend is filled into #1 white opaque hard gelatin capsules (item 9) at atarget weight of 217 mg (range 210 mg to 225 mg). Filled capsules arestored in polyethylene double bags in fiber drums with 2 silica gelpackets between the bags. Physical Product Specifications: Capsule FillWeight (Target): 217 mg Capsule Fill Weight (Range): 210-225 mgDisintegration Time (0.01 N HCl): <10 minutes

While a number of embodiments of this invention have been represented,it is apparent that the basic construction can be altered to provideother embodiments that utilize the invention without departing from thespirit and scope of the invention. All such modifications and variationsare intended to be included within the scope of the invention as definedin the appended claims rather than the specific embodiments that havebeen presented by way of example.

1. A solid pharmaceutical dosage form for oral administrationcomprising: (a) a bisphosphonate, or a pharmaceutically acceptable saltthereof, which bisphosphonate is present in an amount nottherapeutically effective when the bisphosphonate is orally administeredalone; and (b) a modified amino acid carrier, or a pharmaceuticallyacceptable salt thereof, which modified amino acid carrier is present inan amount effective to facilitate absorption of the bisphosphonate inthe gastrointestinal tract such that the bisphosphonate istherapeutically effective; wherein the ratio of bisphosphonate tomodified amino acid carrier is from about 1:30 to about 1:1,respectively.
 2. The dosage form according to claim 1, wherein thebisphosphonate is selected from the group consisting of alendronate,clodronate, etidronate, ibandronate, incadronate, olpadronate,pamidronate, risedronate, titudronate, zoledronate, and pharmaceuticallyacceptable salts thereof.
 3. The dosage form according to claim 2,wherein the bisphosphonate is ibandronate, or a pharmaceuticallyacceptable salt thereof.
 4. The dosage form according to claim 3,wherein the bisphosphonate is ibandronate sodium.
 5. The dosage formaccording to claim 1, wherein the modified amino acid carrier isselected from the group consisting ofN-(8-(2-hydroxybenzoyl)amino)caprylate,N-(10-(2-hydroxybenzoyl)amino)capricate,N-(2-methoxybenzoyl)-3-(4-aminophenyl)proprionate,N-(3-dimethylaminobenzoyl)-3-(4-aminophenyl)butyrate,N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate,N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate,N-(4-(3-cyclohexylproprionyl)amino)butyrate, andN-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, andpharmaceutically acceptable salts thereof.
 6. The dosage form accordingto claim 5, wherein the modified amino acid carrier isN-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptablesalt thereof.
 7. The dosage form according to claim 6, wherein themodified amino acid carrier is sodiumN-(8-(2-hydroxybenzoyl)amino)caprylate.
 8. The dosage form according toclaim 1, wherein the ratio of bisphosphonate to modified amino acidcarrier is such that absorption of the bisphosphonate in thegastrointestinal tract is at least 2 times greater than that of thebisphosphonate when administered alone.
 9. The dosage form according toclaim 3, wherein the amount of ibandronate present is from about 0.25 mgto about 175 mg.
 10. The dosage form according to claim 4, wherein theamount of ibandronate sodium present is such as to be equivalent to fromabout 0.25 mg to about 175 mg of ibandronic acid.
 11. The dosage formaccording to claim 1, wherein the ratio of bisphosphonate to modifiedamino acid carrier is about 1:20, respectively.
 12. The dosage formaccording to claim 1, wherein the ratio of bisphosphonate to modifiedamino acid carrier is about 1:10, respectively.
 13. The dosage formaccording to claim 1, wherein the ratio of bisphosphonate to modifiedamino acid carrier is about 1:5, respectively.
 14. The dosage formaccording to claim 1, further comprising povidone present in an amountfrom about 2% to about 30% by weight of the total composition.
 15. Thedosage form according to claim 14 wherein the povidone is present in anamount from about 10% to about 20%.
 16. The dosage form according toclaim 15 wherein the povidone is present in an amount from about 12% toabout 15%.
 17. A method for treating osteoporosis comprisingadministering to a subject in need thereof a solid pharmaceutical dosageform for oral administration comprising: (a) a bisphosphonate, or apharmaceutically acceptable salt thereof, which bisphosphonate ispresent in an amount not therapeutically effective when thebisphosphonate is orally administered alone; and (b) a modified aminoacid carrier, or a pharmaceutically acceptable salt thereof, whichmodified amino acid carrier is present in an amount effective tofacilitate absorption of the bisphosphonate in the gastrointestinaltract such that the bisphosphonate is therapeutically effective; whereinthe ratio of bisphosphonate to modified amino acid carrier is from about1:30 to about 1:1, respectively.
 18. The method according to claim 17,wherein the bisphosphonate is selected from the group consisting ofalendronate, clodronate, etidronate, ibandronate, incadronate,olpadronate, pamidronate, risedronate, titudronate, zoledronate, andpharmaceutically acceptable salts thereof.
 19. The method according toclaim 18, wherein the bisphosphonate is ibandronate, or apharmaceutically acceptable salt thereof.
 20. The method according toclaim 19, wherein the bisphosphonate is ibandronate sodium.
 21. Themethod according to claim 17, wherein the modified amino acid carrier isselected from the group consisting ofN-(8-(2-hydroxybenzoyl)amino)caprylate,N-(10-(2-hydroxybenzoyl)amino)capricate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)proprionate,N-(3-dimethylaminobenzoyl) -3-(4-aminophenyl)butyrate,N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate, N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate,N-(4-(3-cyclohexylproprionyl)amino)butyrate,N-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, andpharmaceutically acceptable salts thereof.
 22. The method according toclaim 21, wherein the modified amino acid carrier isN-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptablesalt thereof.
 23. The method according to claim 22, wherein the modifiedamino acid carrier is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate. 24.The method according to claim 17, wherein the ratio of bisphosphonate tomodified amino acid carrier is such that absorption of thebisphosphonate in the gastrointestinal tract is at least 2 times greaterthan that of the bisphosphonate when administered alone.
 25. The methodaccording to claim 19, wherein the amount of ibandronate administered isfrom about 0.25 mg to about 75 mg.
 26. The method according to claim 20,wherein the amount of ibandronate sodium administered is such as to beequivalent to from about 0.25 mg to about 75 mg of ibandronic acid. 27.The method according to claim 26, wherein the amount of ibandronatesodium administed daily is such as to be equivalent to from about 0.25mg to about 1.25 mg of ibandronic acid.
 28. The method according toclaim 26, wherein the amount of ibandronate sodium administed monthly issuch as to be equivalent to from about 15 mg to about 75 mg ofibandronic acid.
 29. The method according to claim 17, wherein the ratioof bisphosphonate to modified amino acid carrier is about 1:20,respectively.
 30. The method according to claim 17, wherein the ratio ofbisphosphonate to modified amino acid carrier is about 1:10,respectively.
 31. The method according to claim 17, wherein the ratio ofbisphosphonate to modified amino acid carrier is about 1:5,respectively.
 32. The method according to claim 17, wherein thepharmaceutical dosage form further comprises povidone present in anamount from about 2% to about 30% by weight of the total composition.33. A method for treating hypercalcemia of cancer comprisingadministering to a subject in need thereof a solid pharmaceutical dosageform for oral administration comprising: (a) a bisphosphonate, or apharmaceutically acceptable salt thereof, which bisphosphonate ispresent in an amount not therapeutically effective when thebisphosphonate is orally administered alone; and (b) a modified aminoacid carrier, or a pharmaceutically acceptable salt thereof, whichmodified amino acid carrier is present in an amount effective tofacilitate absorption of the bisphosphonate in the gastrointestinaltract such that the bisphosphonate is therapeutically effective; whereinthe ratio of bisphosphonate to modified amino acid carrier is from about1:30 to about 1:1, respectively.
 34. The method according to claim 33,wherein the bisphosphonate is selected from the group consisting ofalendronate, clodronate, etidronate, ibandronate, incadronate,olpadronate, pamidronate, risedronate, titudronate, zoledronate, andpharmaceutically acceptable salts thereof.
 35. The method according toclaim 34, wherein the bisphosphonate is ibandronate, or apharmaceutically acceptable salt thereof.
 36. The method according toclaim 35, wherein the bisphosphonate is ibandronate sodium.
 37. Themethod according to claim 33, wherein the modified amino acid carrier isselected from the group consisting ofN-(8-(2-hydroxybenzoyl)amino)caprylate,N-(10-(2-hydroxybenzoyl)amino)capricate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)proprionate,N-(3-dimethylaminobenzoyl) -3-(4-aminophenyl)butyrate,N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate, N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate,N-(4-(3-cyclohexylproprionyl)amino)butyrate,N-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, andpharmaceutically acceptable salts thereof.
 38. The method according toclaim 37, wherein the modified amino acid carrier isN-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptablesalt thereof.
 39. The method according to claim 38, wherein the modifiedamino acid carrier is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate. 40.The method according to claim 33, wherein the ratio of bisphosphonate tomodified amino acid carrier is such that absorption of thebisphosphonate in the gastrointestinal tract is at least 2 times greaterthan that of the bisphosphonate when administered alone.
 41. The methodaccording to claim 35, wherein the amount of ibandronate administered isfrom about 5 mg to about 175 mg.
 42. The method according to claim 36,wherein the amount of ibandronate sodium administered is such as to beequivalent to from about 5 mg to about 175 mg of ibandronic acid. 43.The method according to claim 42, wherein the amount of ibandronatesodium administered daily is such as to be equivalent to from about 5 mgto about 25 mg of ibandronic acid.
 44. The method according to claim 36,wherein the amount of ibandronate sodium administered weekly is such asto be equivalent to from about 35 mg to about 175 mg of ibandronic acid.45. The method according to claim 33, wherein the ratio ofbisphosphonate to modified amino acid carrier is about 1:20,respectively.
 46. The method according to claim 33, wherein the ratio ofbisphosphonate to modified amino acid carrier is about 1:10,respectively.
 47. The method according to claim 33, wherein the ratio ofbisphosphonate to modified amino acid carrier is about 1:5,respectively.
 48. The method according to claim 33, wherein thepharmaceutical dosage form further comprises povidone present in anamount from about 2% to about 30% by weight of the total composition.49. A method for treating metastatic bone pain comprising administeringto a subject in need thereof a solid pharmaceutical dosage form for oraladministration comprising: (a) a bisphosphonate, or a pharmaceuticallyacceptable salt thereof, which bisphosphonate is present in an amountnot therapeutically effective when the bisphosphonate is orallyadministered alone; and (b) a modified amino acid carrier, or apharmaceutically acceptable salt thereof, which modified amino acidcarrier is present in an amount effective to facilitate absorption ofthe bisphosphonate in the gastrointestinal tract such that thebisphosphonate is therapeutically effective; wherein the ratio ofbisphosphonate to modified amino acid carrier is from about 1:30 toabout 1:1, respectively.
 50. The method according to claim 49, whereinthe bisphosphonate is selected from the group consisting of alendronate,clodronate, etidronate, ibandronate, incadronate, olpadronate,pamidronate, risedronate, titudronate, zoledronate, and pharmaceuticallyacceptable salts thereof.
 51. The method according to claim 50, whereinthe bisphosphonate is ibandronate, or a pharmaceutically acceptable saltthereof.
 52. The method according to claim 51, wherein thebisphosphonate is ibandronate sodium.
 53. The method according to claim49, wherein the modified amino acid carrier is selected from the groupconsisting of N-(8-(2-hydroxybenzoyl)amino)caprylate,N-(10-(2-hydroxybenzoyl)amino)capricate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)proprionate,N-(3-dimethylaminobenzoyl)-3-(4-aminophenyl)butyrate,N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate,N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate,N-(4-(3-cyclohexylproprionyl)amino)butyrate,N-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, andpharmaceutically acceptable salts thereof.
 54. The method according toclaim 53, wherein the modified amino acid carrier isN-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptablesalt thereof.
 55. The method according to claim 54, wherein the modifiedamino acid carrier is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate. 56.The method according to claim 49, wherein the ratio of bisphosphonate tomodified amino acid carrier is such that absorption of thebisphosphonate in the gastrointestinal tract is at least 2 times greaterthan that of the bisphosphonate when administered alone.
 57. The methodaccording to claim 51, wherein the amount of ibandronate administered isfrom about 5 mg to about 175 mg.
 58. The method according to claim 52,wherein the amount of ibandronate sodium present is such as to beequivalent to from about 5 mg to about 175 mg of ibandronic acid. 59.The method according to claim 49, wherein the ratio of bisphosphonate tomodified amino acid carrier is about 1:20, respectively.
 60. The methodaccording to claim 49, wherein the ratio of bisphosphonate to modifiedamino acid carrier is about 1:10, respectively.
 61. The method accordingto claim 49, wherein the ratio of bisphosphonate to modified amino acidcarrier is about 1:5, respectively.
 62. The method according to claim49, further comprising povidone present in an amount from about 2% toabout 30%, by weight of the total composition.
 63. A method forpreparing a solid pharmaceutical dosage form for oral administrationcomprising admixing: (a) a bisphosphonate, or a pharmaceuticallyacceptable salt thereof, which bisphosphonate is present in an amountnot therapeutically effective when the bisphosphonate is orallyadministered alone; and (b) a modified amino acid carrier, or apharmaceutically acceptable salt thereof, which modified amino acidcarrier is present in an amount effective to facilitate absorption ofthe bisphosphonate in the gastrointestinal tract such that thebisphosphonate is therapeutically effective; such that the ratio ofbisphosphonate to modified amino acid carrier is from about 1:30 toabout 1:1, respectively, and wherein the modified amino acid carrier andthe bisphosphonate are in intimate contact.
 64. The method according toclaim 63, wherein the bisphosphonate is ibandronate, or apharmaceutically acceptable salt thereof.
 65. The method according toclaim 63, wherein the modified amino acid carrier is selected from thegroup consisting of N-(8-(2-hydroxybenzoyl)amino)caprylate,N-(10-(2-hydroxybenzoyl)amino)capricate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)proprionate,N-(3-dimethylaminobenzoyl) -3-(4-aminophenyl)butyrate,N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate,N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate,N-(4-(3-cyclohexylproprionyl)amino)butyrate, andN-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, andpharmaceutically acceptable salts thereof.
 66. The method according toclaim 65, wherein the modified amino acid carrier isN-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptablesalt thereof.
 67. The method according to claim 65, wherein the ratio ofbisphosphonate to modified amino acid carrier is such that absorption ofthe bisphosphonate in the gastrointestinal tract is at least 2 timesgreater than that of the bisphosphonate when administered alone.
 68. Themethod according to claim 65, wherein the amount of ibandronate presentis from about 0.25 mg to about 175 mg.
 69. The method according to claim65, wherein the ratio of bisphosphonate to modified amino acid carrieris about 1:20, respectively.
 70. The method according to claim 65,wherein the ratio of bisphosphonate to modified amino acid carrier isabout 1:10, respectively.
 71. The method according to claim 65, whereinthe ratio of bisphosphonate to modified amino acid carrier is about 1:5,respectively.
 72. The method according to claim 65, wherein the solidpharmaceutical dosage form further comprises povidone present in anamount from about 2% to about 30% by weight of the total composition.